Laminins are a family of large extracellular glycoproteins which display a complex and still unclear repertoire of biological functions. Laminin-2, the isoform involved in congenital muscular dystrophy (CMD), is specifically expressed in the basal lamina of striated muscle and peripheral nerve. As are all members of the laminin family, it is composed of three chains: one heavy (.alpha.2) and two light chains (.beta.1 and .gamma.1) that assemble in a cross-shaped molecule with three short arms and one long arm. The C-terminal ends of each chain interact to form the triple stranded long arm of the molecule, stabilized by disulfide bonds, with a large globular (G) domain contributed to by the .alpha.2-chain. The .alpha.2-chain of laminin consists of 6 domains: I and II are part of the long arm; IIIa, IIIb and V contain cystein-rich EGF-like repeats and are predicted to have rigid rod-like structures; and IVa, IVb and VI are predicted to form globular structures. Laminin .alpha.2-chain has been shown to be a native ligand for .alpha.-dystroglycan, an extracellular component of the dystrophin-associated glycoprotein complex (DGC). This complex constitutes a link between the subsarcolemmal skeleton and the extracellular matrix. A number of components of the DGC have now been shown to be involved in muscular dystrophies suggesting a crucial role of laminin-2 and the components of the DGC in maintaining the integrity of muscle cell function.
Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of autosomal recessive neuromuscular disorders of early onset. In the classic form of CMD, clinical manifestations are limited to skeletal muscle with no clinical involvement of the central nervous system (CNS) although changes in the white matter have been detected by MRI. The histological changes in muscle biopsies consist of connective tissue proliferation, large variation in the size of the muscle fibers as well as some necrotic and regenerating fibers.
Two groups of classical-type CMD cases can be distinguished according to the status of the .alpha.2-chain of laminin-2 (also referred to as merosin) with about half of the cases displaying a deficiency of this protein. However, even these merosin-deficient CMD cases represent a heterogeneous subgroup since some patients display a total deficiency of the .alpha.2-chain of laminin-2 whereas this protein is expressed in others, though at a reduced level. Linkage analyses and homozygosity mapping studies have led to the localization of the CMD locus to chromosome 6q2 (Hillaire et al., Hum. Mol. Genet. 3: 1657-1661 (1994); and Helbling-Leclerc et al., C. R. Acad. Sci. Paris 318: 1245-1252 (1995)), in the region containing the gene encoding the .alpha.2-chain of laminin (LAMA-2) (Vuolteenaho et al., J. Cell Biol. 124: 381-394 (1994)). Recently, mutations affecting this gene have been identified in CMD patients (Helbling-Leclerc et al., Nat. Genet. 11: 216-218 (1995); and Nissinen et al., Am. J. Hum. Genet. 58: 1177-1184 (1996).
The expression of the .alpha.2-chain of laminin-2 is also altered in the dystrophia muscularis (dy) mouse (Michelson et al., Proc. Natl. Acad. Sci. USA. 41: 1079-1084 (1955); Arahata et al., Proc. Japan Acad. 699: 259-264 (1993); Sunada et al., J. Biol. Chem. 269: 13729-13732 (1994); and Xu et al., Proc. Natl. Acad. Sci. USA 91: 5572-5576 (1994)) and its allelic variant (dy.sup.2J). A splice mutation affecting the murine gene encoding this protein, localized on chromosome 10 (Sunada et al., J. Biol. Chem. 269: 13729-13732 (1994)) has recently been identified in the dy.sup.2J mouse, resulting in the expression of a truncated protein (Xu et al., Nat. Genet. 8: 297-301 (1994); and Sunada et al., Hum. Mol. Genet. 4: 1055-1061 (1995)). Interestingly, the dy.sup.2J mouse displays a less severe phenotype than the dy mouse which lacks the laminin .alpha.2-chain.
Diagnostic and therapeutic developments useful in connection with merosin-deficient CMD cases will require a better understanding of the etiology of the disorder at the molecular level. Such understanding will yield diagnostic kits and ultimately methods for therapeutic intervention.